Lymphotoxin-beta receptor signaling
Lymphotoxin-beta receptor (LTBR), a member of the tumor
necrosis factor receptor superfamily, is essential for the development and organization
of secondary lymphoid tissue. The LTBR binds specific
ligands, such as the membrane form of lymphotoxin heterotrimer, Lymphotoxin-Alpha1Beta2
lymphotoxin LT-beta (LTB); and homotrimer
LIGHT. Expression of
TNF-beta/LTB heterotrimer is
restricted to activated hematopoetic cells, whereas LIGHT is
expressed both by hematopoetic and non-hematopoetic cells.
LTBR activates multiple signaling pathways leading to the
expression of adhesion molecules and chemokines, and cell death , , .
LTBR binds to TNF Receptor-Associated Factors
(TRAF2, -3, and
-5) and mediates stimulation of two separate signaling
pathways, leading to activation of distinct NF-kB
(transcriptional factor) complexes , .
After triggering expression of LTBR by
TRAF2 and TRAF5 activate
NIK (NF-kB-Inducing Kinase) .
NIK, in turn, phosphorylates and activates
IKK-alpha (Inhibitor of KappaB Kinase-Alpha). Both proteins
are required for degradation of the NF-kB2 (p52) precursor,
NF-kB2 (p100), to yield the mature p52, which
heterodimerizes with RelB to form NF-kB
p52/RelB heterodimers . NF-kB
p52/RelB involves in the expression of chemokines
CCL19 and CCL21 .
The other NF-kB pathway that leads to the formation of NF-kB
p50/p65 heterodimers, involving the Alpha
(IKK-alpha), Beta (IKK-
beta) and Gamma
(IKK-gamma) subunits of the
IKK complex, can be turned on after
LTBR activation by
TNF-beta/LTB heterotrimer or
LTB. IKK-dependent degradation
of I-kB (NF-kB inhibitor) and subsequent activation of
NF-kB1 (p50) and RelA(p65) is
independent of NIK , . NF-kB1 and NF-kB
p50/p65 regulate a transcription of genes that encode vascular cell
adhesion molecule VCAM1, and interleukins
IL-2 and IL-8 , , .
LIGHT binding to
LTBR also induces JNK/c-Jun activation. All
three TRAFs (TRAF2, -3, and
-5) induce activation of kinases
MKK7 and JNK1/2.
TRAF2 also induces
pathway. JNK1/2 kinases phosphorylate and activate
transcriptional factor c-Jun that regulates expression
of interleukins IL-2 and IL-8
, , , .
In addition, LIGHT causes cell death by apoptosis of
various tumor cells expressing LTBR. Upon the binding of
LIGHT to LTBR,
TRAF2 is first recruited to the receptor followed by
TRAF3 and c-IAP1 (apoptosis
inhibitor 1) recruitment, during which the BIR1 domain of
c-IAP1 is cleaved. Thereby
c-IAP1, which inhibits activity of caspases by direct
interaction with Caspase-9,
-7, and -3, is
inactivated. The LIGHT-LTBR
complex also triggers the mitochondria-mediated apoptosis pathway by an unknown
mechanism, which induces the release of Cytochrom c and
Smac (second mitochondria-derived activator of caspases)
from mitochondria. TRAF3 has been suggested to trigger the
release of Smac from mitochondria. The cytosolic
Smac is then recruited to the receptor via its interaction
with c-IAP1 .
Smac causes ubiquitination and the rapid degradation of
c-IAP1 . Cytochrom
c released from mitochondria promotes the activation of
caspase-9 through APAF-1
(apoptotic protease activating factor) . Caspases cascade
signaling leads to cell death by apoptosis.
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